We will address the hypothesis that different neurodegenerative diseases are caused by the accumulation of distinct proteins with pathogenic conformations (proteopathies). These disorders are a complex biomedical, behavioral, and social problem as they are increasing in frequency, cause major disability, and remain largely untreatable. If the ways in which different proteins damage nerve cells overlap, treatments may be developed to prevent and reverse more than one of these conditions. We have assembled five interactive projects and four essential cores to study the mechanisms by which proteins associated with Alzheimer's, Parkinson's, or Huntington's disease impair neuronal function and survival. The program is multidisciplinary and relies on state-of- the-art technology, including X-ray crystallography, robotic microscopy, transgenic and gene-targeted mouse models, cellular biology, neuropathology, and behavioral neuroscience. Project 1, "Polyglutamine Conformation and Neurodegeneration," aims to differentiate whether visible aggregates or other conformational states of mutant huntingtin are responsible for Huntington's disease-related neurodegeneration. Project 2, "Protein Structure in Apolipoprotein E4-associated Neurodegeneration," will test whether the Alzheimer's disease-promoting effect of apolipoprotein E4 depends on the conformation and stability of this molecule. Project 3, "Apolipoprotein E in Neurobiology: Cellular Mechanisms," will examine whether apolipoprotein E4 promotes Alzheimer's disease-like pathology through amyloid 13peptide (A_)-dependent pathways or via independent mechanisms. Project 4, "Causes and Consequences of _-Synuclein Aggregation," will assess whether pathogenic interactions between A[3 and _- synuclein could contribute to the development of PD and other Lewy body diseases. Project 5, "Mechanisms of A[3- induced Neuronal Deficits," aims to identify the molecular cascades that link the formation of neurotoxic A[3 assemblies to Alzheimer's disease-related cognitive decline and will test whether these cascades can be modulated by apolipoprotein E isoforms and _x-synuclein. The Cores (A: Administrative; B: Tissue Culture; C: Animal; D: Neuropathology/Imaging) will provide the common services necessary to accomplish the goals of the program project. Our studies will shed light on diverse neurodegenerative diseases and could provide the knowledge needed to better treat and prevent them.